Breast and endometrial carcinomas remain major oncological problems. Both types of cancers are considered to be responsive to endocrine therapy. This is particularly true in the case of breast cancer, whether one considers ablative or additive therapy. However, tumor responses to steroid therapy vary significantly among these tumors. In general, for breast carcinoma, only half of the tumors of estrogen receptor (ER)-positive breast cancer patients, assessed by the dextran-coated charcoal assay (DCC assay) (see U.S. Pat. No. 5,030,417; Thibodeau et al., Clin. Chem., 27, 687 (1981)), respond to estrogen (E) therapy. Moreover, 80% of all breast cancer metastases to bone are ER positive. Although the ER and PR (progesterone receptor; Thibodeau et al., Clin. Chem., 27, 687 (1981)) assays currently in use clinically have improved a physician's ability to predict a response to hormonal therapy, the DCC assay has a relatively high false-positive rate (Ingle, Cancer, 53, 766 (1984)). Furthermore, the lack of response to estrogen therapy by many ER-positive patients indicates the need for an assay with estrogen-related markers that have a substantially higher predictive index than the DCC assay.
The breast cancer genes BRCA-1 and BRCA-2 appear to be involved in the inherited susceptibility of breast cancer. Both BRCA-1 and BRCA-2 genes encode polypeptides having homology domains and properties of a granin family of proteins (Schuard et al., Endocrine Reviews, 14, 659 (1993); Steeg, Nat. Gene., 12, 223 (1996); Jensen et al., Nat. Genet., 12, 303 (1996); Holt et al., Nat. Genet., 12, 298 (1996); Wooster et al., Science, 265, 2088 (1995)). Overexpresssion of the BRCA genes inhibits, and underexpression encourages, tumor growth. The p53 gene, a tumor suppressor gene, and the BRCA-1 gene, which exhibits properties of a tumor suppressor gene, are regulated by estrogen in breast cancer cells.
Transforming growth factor-beta (TGB-.beta.) is produced by breast cancer cells and can inhibit breast cancer cell growth (Valverius et al., Cancer Res., 49, 6269 (1989); Knabbe et al., Cell, 48, 417 (1987)). The production and activation of TGF-.beta. is regulated by estrogen, parathyroid hormone, glucocorticoids, and other bone regulatory agents including TGF-.beta. itself (Oursler et al., Endocrinology, 129, 3313 (1991); Oursler et al., Endocrinology, 133, 2187 (1993); Subramaniam et al., J. Cell. Biochem., 57, 52 (1995)). More recently, TGF-.beta. has been implicated in the antiestrogen-induced apoptosis of breast cancer cells (Chen et al., J. Cell, Biochem., 61, 9 (1996)).
Thus, a continuing and urgent need exists for an accurate determinant marker effective to ascertain the most efficacious therapy of breast cancers. In particular, there is a need to identify and isolate estrogen and TGF-.beta. regulated genes, the expression of which are predictive of a breast or endometrial cancer patient's response to steroid therapy or the metastatic potential of these cancers. Moreover, there is also a need to identify and isolate genes that may be tumor suppressor genes for both breast and endometrial carcinomas.